The objective of the proposed research is to examine the role of antigen-specific suppressor cells in the induction and maintenance of immunologic unresponsiveness of both T and B lymphocytes in experimental animals. Experiments will be performed to establish and characterize states of immunologic unresponsiveness lacking suppressor cells. Comparisons of these unresponsive states to a single soluble protein antigen, human gamma globulin, established in the presence or absence of suppressor cells will make possible the investigation of: 1. the effect of suppressor cells on the unresponsive state, 2. the course of this unresponsiveness in the absence of demonstrable suppressor cells, 3. the interaction of suppressor cells with other mechanisms effecting the induction and maintenance of tolerance, 4. the processes which influence the generation, regulation and possible tolerization of suppressor cells, and 5. the means by which both suppressor cells and the unresponsive state can be manipulated. The relationship between the generation and expression of suppressor cells and the course of the unresponsive state will be examined in animals rendered unresponsive at various times in their life cycle: a. during the ontogeny of immunocompetency, b. as immunologically mature, young adults, and 3. during the decline in immunocompetency associated with the aging process. The information obtained in fulfilling the objectives outlined above will be directly applied to the manipulation of the levels of suppressor cells generated by antigenic challenge. Such manipulations may result in immunodepression or immunopotentiation which have broad application to immunogenic responsiveness in defenses against infection, in reactivity to neoplasia and in autoimmune disorders.